Gene expression analysis can reveal the presence of a disease, such as cancer, in a patient, its type, stage, and origin, and whether genetic mutations are involved. Gene expression analysis can also be used to predict the efficacy of a therapy. For example, the National Cancer Institute (NCI) has tested compounds, including chemotherapy agents, for their effect in limiting the growth of 60 human cancer cell lines. NCI has also measured gene expression in those 60 cancer cell lines using DNA microarrays. Various studies have explored the relationship between gene expression and compound effect using the NCI datasets.
The antimetabolite 5-flourouracil (5-FU) is the standard of care in systemic treatment of primary and metastatic colorectal cancer, with further activity in a wide range of solid tumors, including other gastrointestinal malignancies, breast cancer, head and neck cancers, and ovarian carcinomas. It is manufactured not only as 5-FU, but also as an oral agent, capecitabine, and as a prodrug, tegafur (DeVita et al., DeVita, Hellmann, and Rosenberg's Cancer: Principles and Practice of Oncology, 8th ed., Philadelphia, Lippincott Williams and Wilkins, 2005). 5-FU treatment results in a survival benefit in the adjuvant setting of colorectal cancer (Rougier et al., Ann Oncol. 1993; 4 Suppl 2:21-8). Response rates for 5-FU monotherapy in metastatic colorectal cancer are low (10-15%) (Longley et al., Nat. Rev. Cancer 3: 330-338, 2003), therefore it is currently combined with either topoisomerase-1 inhibitor irinotecan as FOLFIRI regimen or platinum-based oxaliplatin as a FOLFOX regimen and targeted EGFR-inhibitor cetuximab according to KRAS-status. Many rivaling factors at the level of both tumor cell characteristics and patient variability may impact the efficacy of 5-FU (Longley et al., supra). After three decades of examining potential predictive biomarkers, the results are mostly far from any clinical realization.
Adjuvant treatment of stage II to III colorectal cancer patients has stagnated, even with many attempts at introducing new drugs in the past decade (Venook et al., Am. Soc. Clin. Oncol. 83-89, 2014). Biomarkers to assist physicians with respect to prognosis, prediction of treatment efficacy, and expected severe toxicities to antineoplastic treatment of colon cancer are and have long been eagerly awaited. Although research on prognostic biomarkers in colon cancer began as early as 1981, few prognostic biomarkers have been implemented clinically except for carcinoembryonic antigen (CEA) (Ichiki et al., Oncology 38: 27-30, 1981) and microsatellite instability (MSI) (Reimers et al., supra), even though many have been examined (Roth et al., Natl. Cancer Inst. 104: 1635-1646, 2012; Bezulier et al., J. Clin. Pharm. Ther. 28: 403-408, 2003; Watanabe et al., N. Engl. J. Med. 344: 1196-1206, 2001; Allegra et al., J. Clin. Oncol. 20: 1735-1743, 2002).
Furthermore, during chemotherapy for cancers, critical time is often lost due to a trial and error approach to finding an effective therapy. In addition, cancer cells often develop resistance to a previously effective therapy. In such situations, patient outcome would be greatly improved by early detection of such resistance. Thus, there is a need in the art for proven methods, kits, and devices that can be used to predict the sensitivity or resistance of cancer patients to treatment with chemotherapeutic drugs.